The Pharmaceutical Research and Manufacturers of America (PhRMA) is pleased to submit these comments in response to the Food and Drug Administration’s (FDA) request for comments on priorities for the development and implementation of solutions to the challenges of antibacterial drug development. PhRMA is a voluntary, nonprofit association that represents the country’s leading innovative biopharmaceutical research and biotechnology companies, which are devoted to discovering and developing medicines that enable patients to live longer, healthier, and more productive lives. Since 2000, PhRMA member companies have invested approximately $550 billion in the search for new treatments and cures, including an estimated $48.5 billion in 2012 alone. PhRMA member companies are committed to the development of innovative, life-saving and life-altering treatments and cures for serious and life-threatening conditions.

PhRMA is committed to helping ensure that patients have access to safe and effective new medicines, and we recognize the particular importance of developing and securing the approval of new antibacterials that can prevent the mortality and debilitating morbidity associated with emerging or resistant pathogens. PhRMA understands that for patients affected by such pathogens, timely access to new medicines can be a matter of life or death. We have, therefore, long supported FDA’s appropriate use of innovative approaches and regulatory flexibility when considering the type and quantity of data required to establish

the safety and efficacy of these medicines—as well as other innovative medicines to address unmet medical needs.

Although PhRMA believes that FDA’s existing regulatory armamentarium is strong, we also recognize that development of new antibacterials represents an urgent and unique challenge that requires special attention. As such, PhRMA applauds the Agency for issuing this request for comments, and we continue to support the Agency as it seeks to implement solutions that encourage and facilitate the development of urgently needed antibacterials. We hope that the Agency finds these comments useful as it seeks to accelerate the development of novel antibacterials. As noted in our comments submitted to the Agency in February 27, 2013 on the proposed Alternative Pathway,1 PhRMA supports FDA’s use of existing regulatory flexibility and the development and revision of guidance to advance novel scientific approaches to facilitate antibacterial drug development. As requested, we have organized our comments by the categories for public comment: 1) novel study designs; 2) prioritized list of proposed draft or final guidance development; and 3) strategies to slow the rate of emerging drug resistance.

2 See generally Rex JH, et al., A comprehensive regulatory framework to address the unmet need for new antibacterial treatments, THE LANCET (Jan. 15, 2013). The authors propose a 4-tiered regulatory framework under which differing quantities of clinical evidence may be required. They also argue that antibacterial drugs are well suited to orthogonal datasets and a totality-of-the-evidence approach and that by providing both dose justification and proof of mechanism (the antibiotic acts through its pharmacological effect on bacteria), the well

I. Novel study designs to expedite the development of new antibacterial drugs

PhRMA shares the Agency’s sense of urgency about the need for innovative antibacterials that provide novel treatment options for patients with drug-resistant or difficult to treat infections. PhRMA believes that innovative use of the existing mechanisms listed below can help to expedite the availability of new treatments for patients. Clarification of FDA’s expectations in guidance, and regulatory flexibility can accelerate the development of antibacterial products. In addition, PhRMA encourages the Agency to address the development of antibacterial preventative therapies, as there is a lack of regulatory guidance where prevention is the principal focus. Furthermore, PhRMA encourages the Agency to consider study designs that facilitate the development of two or more combined entities, whether new or old, to prevent or treat infections.

Clinical trial design. PhRMA believes that FDA can—and should— explore approaches to pre-clinical and clinical trial design and analysis that might foster antibacterial development and approval. This should include, as proposed in a recent article by Rex et al. in the Lancet Infectious Diseases, acceptance of clinical trial designs that account for prior knowledge of effectiveness and respond to the inherent challenges in testing antibacterials.2

As described in the Lancet article, the Agency could approve a new antibiotic, using existing regulatory flexibility under section 505 of the Federal Food, Drug, and Cosmetic Act (FDCA), in any of four scenarios: (A) pursuant to two phase 3 studies; (B) pursuant to one phase 3 study, plus small comparative and descriptive studies; (C) pursuant to small comparative and descriptive studies; or (D) pursuant to animal efficacy studies and adequate human safety studies. Implementation of the proposed framework in the Lancet article through the development of guidance and use of existing regulatory flexibility would permit and encourage the development of innovative antibacterials to address unmet medical needs.

PhRMA believes that FDA should continue to explore and clarify how existing tools (see non-exhaustive list below) may be used to facilitate development and approval of antibacterial treatments that address unmet needs or serious diseases or conditions. PhRMA applauds the Agency for timely issuance of the Draft Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics.3

Accelerated Approval: Approval can be granted on the basis of studies establishing that the drug or biologic “has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the seriousness, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”4 In the context of antibacterial development, PhRMA requests that the Agency further define how surrogate endpoints may be used with the type of endpoints typically used in antibacterial development. For example, PhRMA believes that in nosocomial pneumonia measurement of improvement of oxygenation or other surrogate endpoints are preferable to use of irreversible morbidity and mortality. When considering the strength of evidence required for use of a surrogate endpoint, PhRMA encourages the FDA to account for the seriousness of the condition and the unmet medical need.

“Totality of the evidence” approach: A “totality-of-the-evidence” approach is a risk-based approach to evaluate all available data and information submitted in support of a determination of safety and efficacy of a new medicine. In antibacterial development, a totality-of-the-evidence approach permits the integration of various types of information from pre-clinical and clinical studies (including pharmacometric analysis), and/or externally- or historically-controlled data about a product’s safety and efficacy to reach an overall assessment of the product’s benefit-risk profile for a defined patient population.

Allowing a Single Adequate and Well-controlled Trial, When Scientifically Appropriate: Congress in 1997 amended section 505 of the FDCA to clarify that, based on relevant science, data from a single adequate and well-controlled clinical investigation with confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness.5 FDA’s resulting guidance offers numerous examples of “substantial evidence” grounded in a single adequate and well-controlled trial and independent substantiation.

In this context, it would also be important to offer specific comments on the use of simple trials for some indications when accompanied by more detailed data in other indications. For example, a drug well-characterized in studies of intra-abdominal infection might very reasonably obtain data in nosocomial pneumonia by using a simple trial approach.

Interpretation of data across sites of infection: In the multi-drug resistant, unmet need or other difficult to enroll settings, it will be necessary to collect data across a range of infection sites. In this situation the sample size may be small at each site of infection and Bayesian hierarchical modeling may be used in this context to capitalize on information sharing across sites of infection, so it would be important to provide specific comments on the use of such approaches.

Bayesian Approaches: Bayesian approaches allow for formal inclusion of prior knowledge of effectiveness into trial design and analysis, thereby increasing efficiency of the trial. For example, PhRMA believes consideration should be given to use of Bayesian augmented active controls in Phase 2 and/or 3 to reduce sample size and time of study completion. Consideration should also be given to use of Bayesian methods as a way to make more use of prior knowledge when determining non-inferiority margins. This could be particularly important where it is only feasible to collect data on a small datasets, and may allow some statistical inference to be made to a less conservatively defined margin.

Adaptive Trial Design: An adaptive design clinical trial is one that includes a prospectively planned opportunity for modification of one or more specified aspects of study design and hypotheses based on analysis of data (usually 5 FDAMA § 115(a), amending FDCA § 505(d)(7). interim data) from subjects in the study. 6 Adaptive trial designs can lead to shorter and smaller trials, and consequently more efficient clinical development programs, compared to traditional non-adaptive trial designs. For example, the nature of endpoints used in antibacterial trials readily allow for adaptive randomization. As such, an area worth of further investigation relates to adaptive dose-finding schemes that may be used to minimize exposure to ineffective doses; use of PK/PD models may be utilized in this framework to optimize decision making.

Fast Track: The fast track process is designed to expedite the review of drugs to treat serious conditions that also address an unmet medical need, so they can reach patients earlier. PhRMA appreciates that the FDA has recently issued draft guidance7 to provide recommendations as to how fast track may be applied to qualified infectious disease products.

8 For example, the Agency has the option to designate an antibacterial as a fast track product or a breakthrough therapy. It can use the accelerated approval pathway and apply priority review to expedite its review timeline. An antibacterial may be approved on the basis of a single clinical trial with confirmatory evidence, on the basis of innovative trial designs (e.g., adaptive trials), or on the basis of animal data using a totality-of-the-evidence approach.

In brief, the statutory and regulatory tools and flexibility discussed above — particularly a “totality of the evidence” approach — should be applied to important new antibacterial therapies whenever scientifically and medically appropriate.8 We also urge FDA to implement the related FDASIA requirements intended to facilitate and expedite drug development and approval. This includes new provisions relating to accelerated approval and breakthrough products and the implementation of a structured benefit-risk assessment framework in the new drug approval process, which would help reduce regulatory uncertainty and expedite drug development.

II. Comments on the prioritized list of proposed draft or final guidance development

PhRMA commends the Agency on the recent issuance of Draft Guidance for Industry on Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases as required by Section 806 of FDASIA.9 As the FDA collects comments on the draft guidance via the public comment period, PhRMA strongly encourages the FDA to identify ways to incorporate a broader range of development options for innovative

antibacterials into the draft guidance, including prevention strategies. PhRMA fully agrees with the statement in the draft guidance that it is “appropriate to exercise the broadest flexibility in applying the statutory standards,” and we encourage the FDA to better articulate the breadth of approaches to antibacterial development that the Agency will consider as it seeks to align the development and regulatory process for antibacterials with the seriousness of the disease and unmet medical need. To this point, PhRMA refers the Agency to the article by John Rex et al. in the Lancet Infectious Diseases. 10

As the FDA considers areas for future guidance development or revision, PhRMA strongly encourages the Agency to update guidances in a manner that best enables the Agency to employ its existing regulatory flexibility under section 505 of the FDCA when considering the quantum and type of clinical data necessary for approval of antibacterials. PhRMA applauds the Agency for taking steps towards fulfillment of the requirement in Section 804 of FDASIA for the FDA to “review and, as appropriate, revise not fewer than 3 guidance documents per year” with the publication of the list of guidance documents for public comments. Accordingly, PhRMA provides the following recommendations regarding priority for review and revision of antibiotic-related guidances as well as additional areas for future guidance development (listed in approximate order of highest priority to lowest):

As guidance on individual indications is updated over time, it will be important to avoid situations in which a change in guidance invalidates studies in progress at the time of the change. Programs begun prior to a guidance change should be allowed to progress to completion based on the prior guidance. As a theme spanning all the guidance documents, attention should be paid to the rapidly evolving array of new diagnostic tools that will facilitate both patient selection and identification of causal pathogens. Where appropriate, guidance

should recognize the growing utility of these tools and seek ways to facilitate their development and use.

Even when antibacterials are used appropriately, antimicrobial resistance is an inevitable evolutionary consequence of antibacterial use. This biological fact underscores the importance of a constant supply of new antibacterial medicines to augment existing options. Appropriate use of antibacterial agents helps slow the emergence of antibiotic-resistant organisms, but a sustainable pipeline of safe and effective antibacterials is still urgently needed to successfully treat serious and life-threatening infections. PhRMA stands ready to work with the Agency and other stakeholders to explore effective ways to facilitate antibacterial development and approval using its existing regulatory flexibility under section 505 of the FDCA, and the strengthening of antibacterial stewardship programs designed and operated by health care providers and health care systems. PhRMA recognizes the important role that healthcare provider-led stewardship programs for antibacterials play in slowing the development and spread of resistance, although stewardship will not eliminate or solve the public health crisis.

PhRMA recommends that the FDA remain focused on improving the feasibility and clarity of the drug development process for antibacterials, recognizing that the continuous supply of new antibacterial agents is critical to protecting the public health. PhRMA believes that health care providers and health care systems are ideally positioned and most appropriate to implement antibacterial stewardship programs. These entities have first-hand understanding of the medical needs of the patients they serve and the epidemiological climate in which they work. Therefore, PhRMA believes that stewardship programs designed and operated by health care providers would be the most effective means of addressing stewardship in a manner that is sufficiently flexible to manage current and emerging resistance issues. Importantly, PhRMA believes that stewardship programs should be implemented in a manner that does not interfere with the ability of health care providers to provide empiric treatment to patients in need.11 The protection of the physician-patient relationship and the ability of health care providers to act on their professional judgment to provide timely, individualized care to patients should be a paramount concern when evaluating potential stewardship programs.

11 The Supreme Court has noted that off-label use is an “accepted and necessary corollary of the FDA’s mission to regulate in this area without directly interfering with the practice of medicine.” Buckman Co. v. Plaintiffs’ Legal Comm., 531 U.S. 341, 350 (2001). Further, “FDA*-]approved indications were not intended to limit or interfere with the practice of medicine nor to preclude physicians from using their best judgment in the interest of the patient.” Weaver v. Reagen, 886 F.2d 194, 198-99 (8th Cir.1989) (internal quotation marks omitted).

Finally, PhRMA believes that inclusion of all available data in the label, including any available data obtained from less common sites of infection, is essential to effective antibacterial stewardship. The label should reflect the totality of the data and its limitations, thus allowing the treating physician to make informed decisions about inappropriate use (e.g, via data on lack of penetration to a given site) and use in situations with limited data (e.g., less-studied sites of infection). PhRMA reminds the Agency that the ability to include or require the above components in labeling of antibacterials is within the scope of current FDA authority. In addition, PhRMA recommends that the FDA make use of modern pharmacometric modeling and analysis for breakpoint designations for new antibacterials, subject to review on the basis of new clinical information after approval. Moreover, older antibacterials should be held to the same standards of analysis, such that true comparisons can be made to optimize stewardship judgments by physicians at point-of-care.

IV. Conclusion

PhRMA believes it is vitally important to encourage and facilitate the development and speed the approval of novel antibacterials. PhRMA stands ready to work with all stakeholders to help achieve this important public health goal. PhRMA supports focused attention by FDA on clarifying and expediting the regulatory framework governing antibacterial approval in order to help facilitate an increase in the number of innovative antibacterials available to combat antimicrobial resistance. PhRMA asks the FDA to act with urgency as it seeks to apply existing regulatory flexibility under section 505 of the FDCA when considering the type and quantity of data required to establish the safety and efficacy of new antibacterials and implement new approaches to antibacterial development that are aligned with the seriousness of disease and the unmet medical needs of patients and the broader public.